The aim of this proposal is to identify immunological mechanisms that regulate cartilage homeostasis. A variety of skeletal disorders are caused by defects in cartilage homeostasis including osteochondrodysplasias, osteochondromas, and osteoarthritis. Together, these disorders affect millions of people worldwide and lack effective cures. Our preliminary data reveal a novel mouse model of spontaneous osteochondromas characterized by accumulation of chondrocytes at the growth plates of multiple bones, with no apparent inflammatory infiltrate. This disease occurs in mice with a germline deletion of Erk1 bred to mice with a conditional deletion of Erk2 mediated by CD4cre (DKOCD4 mice). Remarkably, this excessive chondrocyte accumulation appears to be regulated by cells of the immune system. While considerable research has established a role for the immune system in bone metabolism and inflammatory joint disorders, we present the first evidence that osteochondromas and chondrocyte proliferation in the growth plate are regulated by the immune system. First, we demonstrate that Erk2 deletion is mediated by CD4cre, which is only known to be expressed in subsets of immune cells, and does not alter Erk2 expression in chondrocytes. Second, we show osteochondromas develop faster and with a greater severity in DKOCD4 mice that lack T cells and B cells. Third, we found that addition of T cells into mice that develop osteochondromas significantly delayed the onset of tumors. Finally, we demonstrate that treating the DKOCD4 mice with an inflammatory stimulus, or housing them in an environment with known pathogens accelerates development of osteochondromas. Thus, we hypothesize that cells of the immune system are important regulators of chondrocyte homeostasis. An improved understanding of this regulation will be critical for devising novel treatment strategies for disorders caused by cartilage defects. To test our hypothesis, we will first determine which cell types promote osteochondroma formation. Second, we will establish which immune cells suppress development of cartilage tumors. Finally, we will investigate if immune regulation of chondrocyte growth is specifically required during development or whether continual regulation is required to control chondrocyte growth. These experiments will lend valuable insight into the components of the immune response that are critical for regulation of chondrocyte proliferation, which could transform how diseases caused by defective cartilage homeostasis are treated.